Esomeprazole Magnesium: Package Insert and Label Information (Page 5 of 7)

12.5 Pharmacogenomics

CYP2C19, a polymorphic enzyme, is involved in the metabolism of esomeprazole. The CYP2C19*1 allele is fully functional while the CYP2C19*2 and *3 alleles are nonfunctional. There are other alleles associated with no or reduced enzymatic function. Patients carrying two fully functional alleles are extensive metabolizers and those carrying two loss-of-function alleles are poor metabolizers. The systemic exposure to esomeprazole varies with a patient’s metabolism status: poor metabolizers > intermediate metabolizers > extensive metabolizers. Approximately 3% of Caucasians and 15 to 20% of Asians are CYP2C19 poor metabolizers.

Systemic esomeprazole exposures were modestly higher (approximately 17%) in CYP2C19 intermediate metabolizers (IM; n=6) compared to extensive metabolizers (EM; n=17) of CYP2C19. Similar pharmacokinetic differences were noted across these genotypes in a study of Chinese healthy subjects that included 7 EMs and 11 IMs. There is very limited pharmacokinetic information for poor metabolizers (PM) from these studies.

At steady state following once daily administration of esomeprazole 40 mg, the ratio of AUC in poor metabolizers to AUC in the rest of the population (EMs) is approximately 1.5. This change in exposure is not considered clinically meaningful.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of esomeprazole magnesium delayed-release capsules was assessed using studies of omeprazole, of which esomeprazole is an enantiomer. In two 24-month oral carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44, and 140.8 mg/kg/day (about 0.4 to 34 times the human dose of 40 mg/day expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 3.4 times the human dose of 40 mg/day on a body surface area basis) for 1 year, then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of 1 year (94% treated vs. 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs. 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for 2 years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive.

Esomeprazole was negative in the Ames mutation test, in the in vivo rat bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test. Esomeprazole, however, was positive in the in vitro human lymphocyte chromosome aberration test. Omeprazole was positive in the in vitro human lymphocyte chromosome aberration test, the in vivo mouse bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test.

The potential effects of esomeprazole on fertility and reproductive performance were assessed using omeprazole studies. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 34 times the human dose of 40 mg/day on a body surface area basis) was found to have no effect on reproductive performance of parental animals.

13.2 Animal Toxicology and/or Pharmacology

Reproduction Studies

Reproduction studies have been performed in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole [see Use in Specific Populations (8.1)].

Juvenile Animal Study

A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg /kg/day (about 17 to 68 times a daily oral human dose of 40 mg on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole.

14 CLINICAL STUDIES

14.1 Healing of EE in Adults

The healing rates of esomeprazole magnesium delayed-release capsules 40 mg, esomeprazole magnesium delayed-release capsules 20 mg, and omeprazole delayed-release capsules 20 mg (the approved dose for this indication) were evaluated in adult patients with endoscopically diagnosed EE in four multicenter, double-blind, randomized studies. The healing rates at Weeks 4 and 8 were evaluated and are shown in the Table 11:

Table 11: EE Healing Rate (Life-Table Analysis) in Adults with EE Treated with Esomeprazole magnesium Delayed-Release Capsules or Omeprazole Delayed-Release Capsules Once Daily in Four Clinical Studies

N.S. = not significant (p > 0.05)

1 log-rank test vs. omeprazole 20 mg

Study No. of Patients Treatment Groups EE Healing Rates Significance Level1
Week 4 Week 8
1 588 Esomeprazole magnesium delayed-release capsules 20 mg 68.7% 90.6% N.S.
588 Omeprazole 20 mg 69.5% 88.3%
2 654 Esomeprazole magnesium delayed-release capsules 40 mg 75.9% 94.1% p < 0.001
656 Esomeprazole magnesium delayed-release capsules 20 mg 70.5% 89.9% p < 0.05
650 Omeprazole 20 mg 64.7% 86.9%
3 576 Esomeprazole magnesium delayed-release capsules 40 mg 71.5% 92.2% N.S.
572 Omeprazole 20 mg 68.6% 89.8%
4 1,216 Esomeprazole magnesium delayed-release capsules 40 mg 81.7% 93.7% p < 0.001
1,209 Omeprazole 20 mg 68.7% 84.2%

In these same studies of patients with EE, sustained heartburn resolution and time to sustained heartburn resolution were evaluated and are shown in the Table 12:

Table 12: Sustained Resolution1 of Heartburn in Adults with EE Treated with Esomeprazole magnesium Delayed-Release Capsules or Omeprazole Delayed-Release Capsules Once Daily in Four Clinical Studies

1 Defined as 7 consecutive days with no heartburn reported in daily patient diary.

2 Defined as the cumulative proportion of patients who have reached the start of sustained resolution.

3 log-rank test vs. omeprazole 20 mg.

N.S. = not significant (p > 0.05)

Study No. of Patients Treatment Groups Cumulative Percent2 with Sustained Resolution Significance Level3
Day 14 Day 28
1 573 Esomeprazole magnesium delayed-release capsules 20 mg 64.3% 72.7% N.S.
555 Omeprazole 20 mg 64.1% 70.9%
2 621 Esomeprazole magnesium delayed-release capsules 40 mg 64.8% 74.2% p < 0.001
620 Esomeprazole magnesium delayed-release capsules 20 mg 62.9% 70.1% N.S.
626 Omeprazole 20 mg 56.5% 66.6%
3 568 Esomeprazole magnesium delayed-release capsules 40 mg 65.4% 73.9% N.S.
551 Omeprazole 20 mg 65.5% 73.1%
4 1,187 Esomeprazole magnesium delayed-release capsules 40 mg 67.6% 75.1% p < 0.001
1,188 Omeprazole 20 mg 62.5% 70.8%

In these four studies, the range of median days to the start of sustained resolution (defined as 7 consecutive days with no heartburn) was 5 days for esomeprazole magnesium delayed-release capsules 40 mg, 7 to 8 days for esomeprazole magnesium delayed-release capsules 20 mg and 7 to 9 days for omeprazole 20 mg.

There are no comparisons of 40 mg of esomeprazole magnesium delayed-release capsules with 40 mg of omeprazole in clinical trials assessing either healing or symptomatic relief of EE.

14.2 Maintenance of Healing of EE in Adults

Two multicenter, randomized, double-blind placebo-controlled 4-arm trials were conducted in patients with endoscopically confirmed, healed EE to evaluate esomeprazole magnesium delayed-release capsules 40 mg (n=174), 20 mg (n=180), 10 mg (n=168) or placebo (n=171) once daily over six months of treatment.

No additional clinical benefit was seen with esomeprazole magnesium delayed-release capsules 40 mg over esomeprazole magnesium delayed-release capsules 20 mg. Esomeprazole magnesium delayed-release capsules 40 mg once daily is not a recommended regimen for the maintenance of healing of EE in adults.

The percentages of patients that maintained healing of EE at the various time points are shown in the Figures 2 and 3:

Figure 2: Maintenance of Healing Rates by Month (Study 177)

Figure 2: Maintenance of Healing Rates by Month (Study 177)
(click image for full-size original)

s= scheduled visit

Figure 3: Maintenance of EE Healing Rates in Adults by Month (Study 178)

Figure 3: Maintenance of Healing Rates by Month (Study 178)
(click image for full-size original)

s= scheduled visit

Patients remained in remission significantly longer and the number of recurrences of EE was significantly less in patients treated with esomeprazole magnesium delayed-release capsules compared to placebo.

In both studies, the proportion of patients on esomeprazole magnesium delayed-release capsules who remained in remission and were free of heartburn and other GERD symptoms was well differentiated from placebo.

In a third multicenter open label study of 808 patients treated for 12 months with esomeprazole magnesium delayed-release capsules 40 mg, the percentage of patients that maintained healing of EE was 93.7% for six months and 89.4% for one year.

14.3 Symptomatic GERD in Adults

Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in a total of 717 adult patients comparing four weeks of treatment with esomeprazole magnesium delayed-release capsules 20 mg or 40 mg once daily versus placebo for resolution of GERD symptoms. Patients had at least a 6-month history of heartburn episodes, no EE by endoscopy, and heartburn on at least four of the seven days immediately preceding randomization.

The percentage of patients that were symptom-free of heartburn was significantly higher in the esomeprazole magnesium delayed-release capsules groups compared to placebo at all follow-up visits (Weeks 1, 2, and 4).

No additional clinical benefit was seen with esomeprazole magnesium delayed-release capsules 40 mg over esomeprazole magnesium delayed-release capsules 20 mg. Esomeprazole magnesium delayed-release capsules 40 mg once daily is not a recommended regimen for the treatment of symptomatic GERD in adults.

The percent of patients symptom-free of heartburn by day are shown in the Figures 4 and 5:

Figure 4: Percent of Patients Symptom-Free of Heartburn by Day (Study 225)

Figure 4: Percent of Patients Symptom-Free of Heartburn by Day (Study 225) Figure
(click image for full-size original)

Figure 5: Percent of Patients Symptom-Free of Heartburn by Day (Study 226)

Image
(click image for full-size original)

In three European symptomatic GERD trials, esomeprazole magnesium delayed-release capsules 20 mg and 40 mg and omeprazole 20 mg were evaluated. No significant treatment related differences were seen.

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